In liver, most genes are expressed with a porto-central gradient. The transcription factor hepatic nuclear-factor4␣ (HNF4␣) is associated with 12% of the genes in adult liver, but its involvement in zonation of gene expression has not been investigated. A putative HNF4␣-response element in the upstream enhancer of glutamine synthetase (GS), an exclusively pericentral enzyme, was protected against DNase-I and interacted with a protein that is recognized by HNF4␣-specific antiserum. Chromatin-immunoprecipitation assays of HNF4␣-deficient (H4LivKO) and control (H4Flox) livers with HNF4␣ antiserum precipitated the GS upstream enhancer DNA only from H4Flox liver. Identical results were obtained with a histone-deacetylase1 (HDAC1) antibody, but antibodies against HDAC3, SMRT and SHP did not precipitate the GS upstream enhancer. In H4Flox liver, GS, ornithine aminotransferase (OAT) and thyroid hormone-receptor ␤1 ( T he development and maintenance of liver architecture and function is regulated by liver-enriched transcription factors. 1 One of these, hepatic nuclear factor 4␣ (HNF4␣; NR2A1) is expressed at high levels in liver, kidney, intestine, and pancreas 2,3 and binds to the promoter of 12% of genes that are expressed in adult liver. 4 HNF4␣ is an orphan member of the nuclear-receptor superfamily. 2 Depending on chain length and degree of saturation, 5 fatty acyl-coenzyme A thioesters may act as agonistic or antagonistic factors, but whether or not these thioesters function as ligands remains unsettled. 2,[6][7][8] Transcriptional regulation by HNF4␣ is accomplished by interactions with coactivator or corepressor mediators (e.g., GRIP1, SRC-1, CBP/p300, SMRT). 6,7,9,10 The resulting coactivator or corepressor complexes have intrinsic histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity, respectively. Histone modifications play an important role in the regulation of the

LMO2 is a bridging factor within a DNA binding complex and is required for definitive haematopoiesis to occur. The developmental stage of the block in haematopoietic specification is not known. We show that Lmo2−/− mouse embryonic stem cells differentiated to Flk-1+ haemangioblasts, but less efficiently to haemogenic endothelium, which only produced primitive haematopoietic progenitors. Genome-wide approaches indicated that LMO2 is required at the haemangioblast stage to position the TAL1/LMO2/LDB1 complex to regulatory elements that are important for the establishment of the haematopoietic developmental program. In the absence of LMO2, the target site recognition of TAL1 is impaired. The lack of LMO2 resulted in altered gene expression levels already at the haemangioblast stage, with transcription factor genes accounting for ∼15% of affected genes. Comparison of Lmo2−/− with Tal1−/− Flk-1+ cells further showed that TAL1 was required to initiate or sustain Lmo2 expression.

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